Viral replication relates to the formation of viruses during the infection process in the target host cells, which includes translation of viral RNAs by the endogenous machinery. In particular, many viral RNAs are translated and eventually processed through post-translational modifications before being exported outside of the nucleus.
The identification of compounds for treating or preventing a viral infection or a virus-related condition in an individual has led to the development of novel therapies.
Among virus-related conditions, AIDS has developed into a worldwide pandemic. Current therapies have succeeded in controlling the disease but long-term use of Anti-Retroviral Therapy (ART), which is a combination of 3TC, Raltegravir and tenofovir, is limited by issues of drug resistance and side effects.
What is more, those compounds do not necessarily inhibit the replication of viral strains harbouring mutations, which is prone to confer the development of resistant strains.
In particular, for HIV infections, the current ART drugs need to be taken for life and only attenuate the disease without curing it. One reason is that current Human Immunodeficiency Virus (HIV) therapies reduce viral load during treatment but titers rebound after treatment is discontinued, which is one of the consequences of virus latency.
Access to Highly Active Anti-Retroviral Therapy (HAART), based upon the combination of HIV protease and reverse transcriptase inhibitors, has dramatically changed the prognosis of HIV infection. As a result, HIV is considered as a chronic disease in developed countries. However, long-term use of HAART is limited by issues of drug resistance and side effects.
For example, resistance to new classes of anti-HIV/AIDS drugs such as Raltegravir® (integrase inhibitor) and Enfuvirtide® (entry inhibitor) has already been observed.
Alternatives to ART, for example including a combination 3TC-Tenofovir-Raltegravir and AZT (HAART), have thus been proposed.
One indole derivative (IDC16) was discovered to interfere with splicing enhancer activity of the SR protein splicing factor SRSF1 (see for reference Tazi et al. Alternative splicing: regulation of HIV-1 multiplication as a target for therapeutic action. FEBS J. 277, 867-876 (2010)). IDC16 is a planar fused tetracyclic indole compound. This compound suppresses the production of key viral proteins, thereby compromising subsequent synthesis of full-length HIV-1 pre-mRNA and assembly of infectious particles.
In order to minimize the risk that these indole derivatives intercalate between DNA bases, alternative compounds have been developed, that are particularly effective in treating diseases related to the splicing process, but which, in a surprising manner, have a cellular toxicity that is clearly less than the indole derivatives of the prior art.
WO2010/143169 reports compounds which have been found to be effective in treating AIDS and other diseases resulting from changes in splicing processes.
Such molecules, and in particular those in which the polyaromatic nucleus is further substituted by a positively charged (protonated aminoalkyl) side chain, have also been studied as potential anticancer agents (see also WO2010/143168). The guiding principle is that they intercalate DNA and exhibit cytotoxic effects by interfering with the function of DNA processing enzymes such as topoisomerase I and II. Unfortunately, this mechanism of action can still lead to adverse side effects.
Therefore, there is a continuing need for new compounds, in particular those acting through new and as yet unexplored mechanisms of action to treat or prevent viral infections, and more particularly to achieve HIV infection cure.
There also remains a need for compounds which deliver a long lasting reduction of the viral load after treatment termination, in particular for treating virus-infections which are associated with chronic treatment, and/or for targeting latent virus reservoirs.
There also remains a need for compounds with a large spectrum of action, but which are not prone to confer the development of resistant strains, and/or which do not lead to adverse effects.
There also remains a need for compounds which can be less frequently administered over a shorter period, or at longer intervals, than standard treatments; providing the potential to reduce healthcare costs and offer broader access to treatment.
Methods for screening compounds which are efficient for treating or preventing viral infections and virus-related conditions have been reported in the Art.
Recently, Taniguchi et al. (HIV-1 Rev protein specifies the viral RNA export pathway by suppressing TAP/NXF1 recruitment. Nucleic Acids Res. 42, 6645-6658 (2014)) has speculated that the remodeling activity of viral proteins Rev and Rex could be used as a target for anti-retroviral therapy, respectively for HIV and Human T-Lymphotropic Virus (HTLV). However, this document failed to identify compounds useful for therapy or prevention.
Thus, there remains a need for novel methods for screening compounds for treating or preventing a viral infection or a virus-related condition in an individual.
In particular, there remains a need for novel methods for eradicating a viral infection or a virus-related condition in an individual, including for eradicating HIV and/or as a cure for HIV.